Group A Streptococcus pyogenes (GAS) is the most frequent bacterial cause of suppurative infections in humans. S. pyogenes usually produce diseases of the skin and respiratory tract, which may lead to serious sequelae like rheumatic fever and glomerulonephritis. GAS results in an estimated 35 million infections each year in the United States of America and Europe. These infections occur predominantly in school-aged children and adolescents, and are mainly present in the upper respiratory tract, resulting in ‘Strep throat’. This is not life threatening and usually treatable with antibiotics, however such large numbers of affected puts considerable burden on healthcare resources. A number of complications have been reported to occur subsequent to the primary infection, including in some cases invasive, life threatening diseases. GAS infections cause a variety of clinical conditions, ranging from uncomplicated pharyngitis and pyoderma to the less common, more serious deep tissue infections and streptococci toxic shock syndrome. Untreated Strep pharyngitis may trigger acute rheumatic fever (ARF) which is a serious sequelae of GAS and has had a remarkable resurgence in the developing countries within the last 10 years. In addition, the incidence of ARF has remained high and rheumatic carditis remains the leading cause of heart disease in children around the world.
S. pyogenes express one or more surface-associated fibrillar proteins, called M proteins, which are the major virulence factor conferring bacterial resistance to phagocytosis. Antibodies (Abs) directed against these M proteins have been demonstrated to mediate immunity to GAS.
There are currently more than 100 different antigenically distinguishable M proteins. The most severe types of S. pyogenes infections have been reported to be associated with M1 and M3 serotypes although other strains are also responsible. The M-types can be loosely classified into rheumatogenic and non-rheumatogenic strains. The M proteins belong to a large family of structurally related proteins which includes the Emm, Enn and Mrp proteins. The M proteins have affinity for several plasma proteins, including fibrinogen, IgG, IgA, complement factor H (fH), factor H like protein 1 (FHL-1) and C4 binding protein (C4BP). It has been suggested that bacterial binding of these plasma proteins contributes to the anti-phagocytic properties displayed by most M proteins.
S. pyogenes is a potent activator of the complement system. Binding of complement regulatory proteins by streptococcal M proteins could contribute to the inhibition of C3 deposition on the streptococcal surface, providing a mechanism by which M proteins protect the bacteria from phagocytosis by the polymorphonuclear leukocytes (PMN) which accumulate during inflammation. The interaction between fH and M proteins represents the paradigm of how M proteins protect bacteria from complement attack and phagocytosis.
Current vaccine strategies focus on the outer membrane M proteins, due to their ability to confer resistance to phagocytosis. The M proteins may also induce harmful host immune responses through their ability to induce cross-reactive antibody and T cell responses in humans. Added to the variability and number of these proteins, the development of an effective vaccine against a variety of serotypes has been problematic. Although opsonic antibodies directed against the N terminus of the M protein are mainly responsible for serotype immunity, more than 100 serotypes exist. An effective vaccine would provide a cost effective means of preventing disease and help reduce the increased incidence of microbial antibiotic resistance (in other bacteria) which occurs from over dependence on antibiotic therapies.
The most significant impediment to the use of synthetic peptides as vaccines (parenteral delivery) has been that they are only weakly or non-immunogenic when injected by themselves into animals. This property has necessitated the use of carriers, usually large highly immunogenic proteins to which the peptides are covalently coupled. Selecting a carrier protein for peptide vaccines is problematic. The well known and widely used Tetanus and Diphtheria toxoids are both associated with carrier suppression in adults because of prior immunisation with proteins that are routinely administered alone (eg tetanus). Besides insufficient titres against the various peptides, the development of the conjugates can be both expensive and time consuming.
Since the upper respiratory tract represents the port of entry for GAS-infection, the elicitation of an efficient mucosal response is desirable. It is known that the local IgA response plays a critical role in the elicitation of protective immunity against GAS. In general, it is difficult to induce a secretory, and also systemic, immunity when using the mucosal route for a subunit (peptide) vaccine without added adjuvant.